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`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20050158377Al
`
`(19) United States
`(12) Patent Application Publication
`Popp
`
`(10) Pub. No.: US 2005/0158377 A1
`Jul. 21, 2005
`(43) Pub. Date:
`
`(54) DERMATOLOGIC SOFT GEL
`COMPOSITIONS
`
`Related U.S. Application Data
`
`(76)
`
`Inventor: Karl F. Popp, New York, NY (US)
`
`(60) Provisional application No. 60/537,288, filed on Jan.
`20, 2004.
`
`Correspondence Address:
`NATH & ASSOCIATES, PLLC
`Sixth Floor
`1030 15th Street, N.W.
`Washington, DC 20005 (US)
`
`(21)
`
`Appl. No.:
`
`11/037,120
`
`(22) Filed:
`
`Jan. 19,2005
`
`Publication Classification
`
`(51)
`Int. Cl? ....................................................... A61K 9/48
`(52) U.S. Cl. .............................................................. 424/451
`
`ABSTRACT
`(57)
`Orally administrable softgels or soft gelatin capsules and fill
`compositions therefore for use in treating various dermato(cid:173)
`logical conditions. These compositions are also particularly
`useful for treating children or patients of at least 55 years of
`age.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1018, Pg. 1 of 14
`
`

`

`US 2005/0158377 A1
`
`Jul. 21, 2005
`
`1
`
`DERMATOLOGIC SOFT GEL COMPOSITIONS
`
`[0001] This application claims priority to U.S. Provisional
`Patent Application Ser. No. 60/537,288, filed on Jan. 20,
`2004, the contents of which are hereby incorporated by
`reference in their entirety.
`
`FIELD OF THE INVENTION
`
`[0002] The present subject matter relates to orally admin(cid:173)
`istrable softgels or soft gelatin capsules and fill compositions
`therefore for use in treating various dermatological condi(cid:173)
`tions. These compositions are particularly useful for treating
`children, patients of at least 55 years of age, and females.
`
`BACKGROUND OF THE INVENTION
`
`[0003] The topical administration of various pharmaco(cid:173)
`logically active agents to treat various dermatological dis(cid:173)
`orders has long been known in the art. The accessibility of
`the skin and the opportunity it provides for application of
`topical preparations over a prolonged period of time have
`resulted in an increasing use of topical drug delivery systems
`over the past number of years. Typically, these topical
`dosage forms can be in liquid, semisolid, or solid form.
`
`[0004] Drugs have typically been applied to the skin in
`this manner to elicit one or more of four general effects: an
`effect on the skin surface, an effect within the stratum
`corneum, a more deep-seated effect requiring penetration
`into the epidermis and dermis, or a systemic effect resulting
`from delivery of a sufficient amount of drug through the
`epidermis and the dermis to the vasculature to produce
`therapeutic systemic concentrations.
`
`[0005] However, the penetration of a drug into the viable
`epidermis and dermis when applied in a topical dosage form
`may sometimes be difficult to achieve. Further, even if drug
`penetration is achieved, the drug may only be delivered to
`the local area where the composition is applied, rather than
`regionally or systemically. Accordingly, topical composi(cid:173)
`tions are generally not optimal in treating many dermato(cid:173)
`logical disorders that exhibit certain regional or systemic
`effects.
`
`[0006] Topical pharmaceutical dosage forms may have the
`further disadvantage of exhibiting side effects on applica(cid:173)
`tion, such as irritation to sensitive skin areas. Such irritation
`is often due to the presence of preservatives to maintain the
`stability of the active agent in the topical dosage form.
`Maintaining drug stability in topical compositions at times
`can be a very difficult endeavor, making preservatives a very
`common and necessary ingredient in many topical compo(cid:173)
`sitions.
`
`[0007] Further, topical compositions at times have to
`remain in contact with the skin for an extended period of
`time to release sufficient amounts of the active agent to the
`skin and exert the desired pharmacological effect against a
`dermatological disorder. However, it may be difficult to
`formulate a topical composition that remains on the skin for
`this extended period of time without wearing or rubbing off
`during the wearers regular daily activities. Further, topical
`compositions that are sufficiently robust to remain on the
`skin for extended periods of time often have disadvantages
`in that they may not be readily absorbed by the skin, they
`may tend to block skin pores, they may be greasy in nature,
`and they may be difficult to wash off the skin.
`
`[0008] To overcome some of these problems associated
`with certain topical treatments of dermatological disorders,
`many drugs may be administered in an oral dosage form.
`The most common oral dosage forms are tablets and cap(cid:173)
`sules. Tablets and capsules may be prepared from the
`compression of solid ingredients, in powder form or other(cid:173)
`wise. However, an oral dosage form such as a tablet or
`capsule formed via compression oftentimes results in a large
`amount of degradates of the active ingredient.
`
`[0009] Further, solid oral dosage forms may cause irrita(cid:173)
`tion upon administration due to the presence of the active
`agent in a powdery, crystal form. This powdery, crystal form
`of the active ingredient likewise may make it difficult to
`achieve an optimal, controlled dissolution and absorption of
`the active agent after administration. It is oftentimes difficult
`to attain a consistent bioavailability of the active agent due
`to this powdery crystal form.
`
`[0010] Most tablets also require the use of a diluent, or a
`bulking agent, to make the tablet a practical size for com(cid:173)
`pression. Similarly, tablets oftentimes contain other excipi(cid:173)
`ents such as binders, lubricants, glidants, and disintegrants
`to permit formation of the tablet, as well as to aid in drug
`delivery. However, the presence of these additional ingre(cid:173)
`dients may have an adverse effect on both the patient and the
`stability of the active ingredients, depending on the agent
`used.
`
`[0011] Additionally, certain hard tablets and capsules are
`poor delivery devices for hydrophobic drugs. Hydrophobic
`drugs generally do not dissolve readily in water, gastric
`fluid, or intestinal fluid. When they are compounded in solid
`dosage forms, the dissolution rate may be slow, absorption
`may vary, and the bioavailability may be incomplete.
`
`[0012] Hard tablets and hard capsules are also difficult for
`certain patients, particularly certain young and old patients,
`as well as female patients, to swallow. This is due to their
`hard, compact nature, which results in a rough exterior that
`may easily get caught in the mouth or throat. Accordingly,
`there remains a need for an additional dosage form easily
`administrable to young, old, and female human patients that
`is effective for the treatment of dermatological disorders.
`
`[0013] Soft gel capsules, or softgels, are known in the art
`as alternative dosage forms to those described above, but not
`necessarily for the treatment of dermatological disorders.
`For example, U.S. Pat. No. 5,587,149 discloses such a
`softgel formulation for water-soluble active ingredients,
`such as ascorbic acid (vitamin C), where the fill material
`comprises an emulsion of which a first phase includes
`polyethylene glycol (into which the water-soluble active
`ingredient is dissolved) and the second phase includes a
`silicone fluid.
`
`[0014] Likewise, U.S. Pat. No. 6,251,426 discloses a soft
`gelatin capsule that contains a highly concentrated solution
`of ibuprofen. However, this patent does not disclose the
`ability of softgels to deliver active agents useful in treating
`dermatological disorders.
`
`[0015] U.S. Pat. No. 5,200,191 discloses a softgel com(cid:173)
`position containing retinol for topical application to the skin.
`The disclosed softgel provides a single use method for
`dispensing the product, wherein the softgel contains a twist(cid:173)
`off or other removable feature at one end for dispensing the
`fill material encompassed therein. However, since the active
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1018, Pg. 2 of 14
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`

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`US 2005/0158377 Al
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`Jul. 21, 2005
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`2
`
`agent in the disclosed softgel is applied topically to the skin,
`this dosage form is very similar to the topical dosage forms
`previously discussed.
`
`[0020]
`In another preferred embodiment, the present sub(cid:173)
`ject matter relates to a method of treating a dermatological
`disorder in a mammal, comprising:
`
`[0016] One oral softgel known in the art for the treatment
`of dermatological disorders is Accutane®, a softgel avail(cid:173)
`able from Hoffmann-La Roche, New Jersey, containing the
`active ingredient isotretinoin, a known retinoid. The soft gel
`dosage form is used to protect the isotretinoin during manu(cid:173)
`facturing, as retinoids as a class of compounds must be
`protected from oxygen to prevent oxidation. However, this
`softgel composition does not possess any advantages over,
`e.g., a topical composition containing isotretinoin with
`respect to the actual delivery of the drug to a patient. In fact,
`since the isotretinoin is contained in the Accutane® softgel
`in a liquid suspension, it has a half life after administration
`of about 90 hours, resulting in a high possibility of adverse
`side effects.
`
`[0017] Accordingly, there remains a need in the art for
`methods of treating certain dermatological disorders by
`administering a composition that can effectively deliver an
`active agent to the body for the treatment of the dermato(cid:173)
`logical disorder. Such a method would provide an alternative
`to topical dosage forms and compressed oral dosage forms
`such as tablets and capsules by effectively administering a
`drug orally for the treatment of dermatological disorders.
`There further remains a need for treating dermatological
`disorders in young, old, and female patients by administer(cid:173)
`ing an oral composition that is easily and readily taken by
`these patient groups. The present subject matter addresses
`these needs.
`
`SUMMARY OF THE INVENTION
`
`[0018] The present subject matter relates generally to a
`method of treating a dermatological disorder in a mammal.
`This method is achieved by administering to the mammal a
`soft gel capsule providing a therapeutically effective amount
`of a pharmacologically active agent. The soft gel capsule
`preferably comprises an internal, non-aqueous liquid phase
`and an external gelatin and/or soft cellulose layer. The
`internal, non-aqueous liquid phase may comprise a solution
`or suspension of the pharmacologically active agent having
`a purity of at least 90% and a concentration of degradation
`product(s) less than about 10% of the starting concentration
`of the pharmacologically active agent. This purity and
`concentration of degradation product(s) of the active agent
`are preferably sufficient to permit safe treatment of the
`dermatological disorder and provide improved bioavailabil(cid:173)
`ity of the pharmacologically active agent.
`
`[0019]
`In a preferred embodiment, the pharmacologically
`active agent is selected from the group consisting of anti(cid:173)
`biotics, antiinfectives, antimycotic agents, steroids, antihis(cid:173)
`tamines, antiparasitic agents, immunomodulators, antisense
`agents, antiviral agents, treatments for hypo- and hyper-skin
`pigmentation disorders, antipsoriatic agents, keratolytic
`agents, immunosuppressants, DNA synthesis inhibitors,
`cytotoxic agents, antithyroid agents, monoclonal antibody
`regulators, TNF alpha antagonists, immunoglobulins, meta(cid:173)
`bolic regulators, antiangiogenic agents, kinase regulators,
`hormones, photodynamic agents, protease inhibitors, anxi(cid:173)
`olytics, cell growth regulators, enzymes, prostaglandins,
`peptides, analgesics, salts thereof, derivatives thereof, and
`mixtures thereof.
`
`[0021] orally administering to said mammal a soft gel
`capsule providing improved bioavailability of a
`pharmacologically active agent comprising:
`
`[0022] an internal, non-aqueous liquid phase com(cid:173)
`prising a solution or suspension of a single, hydro(cid:173)
`phobic, pharmacologically active agent effective to
`treat said dermatological disorder having a purity of
`at least 90% and a concentration of degradation
`product(s) less than about 10% of the starting con(cid:173)
`centration of said hydrophobic pharmacologically
`active agent, wherein said purity and concentration
`of degradation product(s) are sufficient to permit safe
`treatment of said dermatological disorder; and
`
`[0023] an external gelatin layer comprising gelatin,
`soft cellulose, or a mixture thereof and additional
`components selected from the group consisting of an
`additional gelling agent, a plasticizer, water, a colo(cid:173)
`rant, an antioxidant, a fiavorant, and mixtures
`thereof;
`
`[0024] wherein said hydrophobic pharmacologically
`active agent is selected from the group consisting of
`antiinfectives, steroids, a salt thereof, a derivative
`thereof, and mixtures thereof.
`
`[0025]
`In yet another preferred embodiment, the present
`subject matter relates to a method of treating a dermatologi(cid:173)
`cal disorder in a mammal, comprising:
`
`[0026] orally administering to said mammal a soft gel
`capsule providing improved bioavailability of a
`pharmacologically active agent comprising:
`
`[0027] an internal, non-aqueous liquid phase having
`a pH of from about 3 to about 9 when combined with
`an aqueous medium comprising a solution or sus(cid:173)
`pension of a single, hydrophobic, pharmacologically
`active agent effective to treat said dermatological
`disorder and one or more fatty acids or derivatives
`the group consisting of
`thereof selected from
`omega-3 fatty acids, DHA, docosapentaenoic acid,
`tetracosapentaenoic acid, tetracosahexaenoic acid,
`monounsaturated fatty acids, polyunsaturated fatty
`acids, saturated fatty acids, trans fatty acids, deriva(cid:173)
`tives thereof, and mixtures thereof, said single phar(cid:173)
`macologically active agent comprising a hydropho(cid:173)
`bic antiinfective agent or a salt or derivative thereof
`having a purity of at least 90% and a concentration
`of degradation product(s) less than about 10% of the
`starting concentration of said hydrophobic antibiotic
`agent, wherein said purity and concentration of deg(cid:173)
`radation product(s) are sufficient to permit safe treat(cid:173)
`ment of said dermatological disorder; and
`
`[0028] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`
`[0029]
`In still another preferred embodiment, the present
`subject matter relates to a method of treating a dermatologi(cid:173)
`cal disorder in a mammal, comprising:
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1018, Pg. 3 of 14
`
`

`

`US 2005/0158377 Al
`
`Jul. 21, 2005
`
`3
`
`[0030] orally administering to said mammal a soft gel
`capsule providing improved bioavailability of doxy(cid:173)
`cycline or a salt or derivative thereof comprising:
`[0031] an internal, non-aqueous liquid phase having
`a pH of from about 3 to about 9 when combined with
`an aqueous medium comprising a solution or sus(cid:173)
`pension of doxycycline or a salt or derivative thereof
`as a sole active ingredient effective to treat said
`dermatological disorder and one or more fatty acids
`or derivatives thereof selected from the group con(cid:173)
`sisting of omega-3 fatty acids, DHA, docosapen(cid:173)
`taenoic acid, tetracosapentaenoic acid, tetracosa(cid:173)
`hexaenoic acid, monounsaturated
`fatty acids,
`polyunsaturated fatty acids, saturated fatty acids,
`trans fatty acids, derivatives thereof, and mixtures
`thereof, said doxycycline having a purity of at least
`95% and a concentration of degradation product(s)
`less than about 5% of the starting concentration of
`said doxycycline, wherein said purity and concen(cid:173)
`tration of degradation product(s) are sufficient to
`permit safe treatment of said dermatological disor(cid:173)
`der; and
`[0032] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`[0033]
`In an alternative preferred embodiment, the present
`subject matter relates to a method of treating a dermatologi(cid:173)
`cal disorder in a mammal, comprising:
`[0034] orally administering to said mammal a soft gel
`capsule providing improved bioavailability of a
`hydrophobic pharmacologically active agent com(cid:173)
`prising:
`[0035] an internal, non-aqueous liquid phase com(cid:173)
`prising a solution or suspension of a single hydro(cid:173)
`phobic pharmacologically active agent or a salt or
`derivative thereof effective to treat said dermatologi(cid:173)
`cal disorder and one or more fatty acids or deriva(cid:173)
`tives thereof selected from the group consisting of
`omega-3 fatty acids, docosahexaenoic acid (DHA),
`docosapentaenoic acid, tetracosapentaenoic acid, tet(cid:173)
`racosahexaenoic acid, monounsaturated fatty acids,
`polyunsaturated fatty acids, saturated fatty acids,
`trans fatty acids, derivatives thereof, and mixtures
`thereof, said hydrophobic pharmacologically active
`agent having a purity of at least 90% and a concen(cid:173)
`tration of degradation product(s) less than about 10%
`of the starting concentration of said hydrophobic
`pharmacologically active agent, wherein said purity
`and concentration of degradation product(s) are suf(cid:173)
`ficient to permit safe treatment of said dermatologi(cid:173)
`cal disorder; and
`[0036] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`[0037]
`In a further alternative embodiment, the present
`subject matter relates to a method for treating a human
`patient having an age in excess of at least 55 years, com(cid:173)
`prising:
`
`[0038] orally administering to said human patient in
`need thereof a soft gel capsule providing improved
`bioavailability of a pharmacologically active agent
`comprising:
`[0039] an internal, non-aqueous liquid phase com(cid:173)
`prising a solution or suspension of a pharmacologi(cid:173)
`cally active agent having a purity of at least 90% and
`a concentration of degradation product(s) less than
`about 10% of the starting concentration of said
`pharmacologically active agent and one or more fatty
`acids or derivatives thereof, wherein said purity and
`concentration of degradation product(s) are sufficient
`to permit safe treatment of said human patient and
`provide improved bioavailability of said pharmaco(cid:173)
`logically active agent; and
`[0040] an external gelatin and/or soft cellulose layer;
`[0041] wherein said pharmacologically active agent
`is selected from the group consisting of antibiotics,
`antiinfectives, antimycotic agents, steroids, antihis(cid:173)
`tamines, antiparasitic agents, immunomodulators,
`antisense agents, antiviral agents, treatments for
`hypo- and hyper-skin pigmentation disorders, antip(cid:173)
`soriatic agents, keratolytic agents, immunosuppres(cid:173)
`sants, DNA synthesis inhibitors, cytotoxic agents,
`antithyroid agents, monoclonal antibody regulators,
`TNF alpha antagonists, immunoglobulins, metabolic
`regulators, antiangiogenic agents, kinase regulators,
`hormones, photodynamic agents, protease inhibitors,
`anxiolytics, cell growth regulators, enzymes, pros(cid:173)
`taglandins, pep tides, analgesics, salts thereof, deriva(cid:173)
`tives thereof, and mixtures thereof.
`[0042]
`In yet another alternative embodiment, the present
`subject matter relates to a method of treating a dermatologi(cid:173)
`cal disorder in a human patient having an age in excess of
`at least 55 years, comprising:
`[0043] orally administering to said human patient in
`need thereof a soft gel capsule providing improved
`bioavailability of a tetracycline comprising:
`[0044] an internal, non-aqueous liquid phase having
`a pH of from about 3 to about 9 when combined with
`an aqueous medium comprising a solution or sus(cid:173)
`pension of a tetracycline or a salt or derivative
`thereof as a sole active ingredient effective to treat
`said dermatological disorder and one or more fatty
`acids or derivatives thereof selected from the group
`consisting of omega-3 fatty acids, docosahexaenoic
`acid (DHA), docosapentaenoic acid, tetracosapen(cid:173)
`taenoic acid, tetracosahexaenoic acid, monounsat(cid:173)
`urated fatty acids, polyunsaturated fatty acids, satu(cid:173)
`rated fatty acids,
`trans fatty acids, derivatives
`thereof, and mixtures thereof, said tetracycline hav(cid:173)
`ing a purity of at least 90% and a concentration of
`degradation product(s) less than about 10% of the
`starting concentration of said tetracycline, wherein
`said purity and concentration of degradation prod(cid:173)
`uct(s) are sufficient to permit safe treatment of said
`human patient; and
`[0045] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1018, Pg. 4 of 14
`
`

`

`US 2005/0158377 Al
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`Jul. 21, 2005
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`4
`
`[0046]
`In still another preferred embodiment, the present
`subject matter relates to a soft gel capsule suitable for oral
`administration to a human and providing improved bioavail(cid:173)
`ability of a dermatologically effective active agent compris(cid:173)
`ing:
`
`[0047] an internal, non-aqueous liquid phase having
`a pH of from about 3 to about 9 when combined with
`an aqueous medium comprising a solution or sus(cid:173)
`pension of a dermatologically effective active agent
`or a salt or derivative thereof and one or more fatty
`acids or derivatives thereof selected from the group
`consisting of omega-3 fatty acids, DHA, docosap(cid:173)
`entaenoic acid, tetracosapentaenoic acid, tetracosa(cid:173)
`hexaenoic acid, monounsaturated fatty acids, poly(cid:173)
`unsaturated fatty acids, saturated fatty acids, trans
`fatty acids, derivatives thereof, and mixtures thereof,
`said dermatologically active agent having a purity of
`at least 90% and a concentration of degradation
`product(s) less than about 10% of the starting con(cid:173)
`centration of said dermatologically active agent,
`wherein said purity and concentration of degradation
`product(s) are sufficient to permit safe treatment of
`said human patient; and
`
`[0048] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`
`[0049]
`In a further preferred embodiment, the present
`subject matter relates to a soft gel capsule suitable for oral
`administration to a human and providing improved bioavail(cid:173)
`ability of a tetracycline comprising:
`
`[0050] an internal, non-aqueous liquid phase having
`a pH of from about 3 to about 9 when combined with
`an aqueous medium comprising a solution or sus(cid:173)
`pension of a tetracycline or a salt or derivative
`thereof as a sole active ingredient effective to treat a
`dermatological disorder and one or more fatty acids
`or derivatives thereof selected from the group con(cid:173)
`sisting of omega-3 fatty acids, docosahexaenoic acid
`(DHA), docosapentaenoic acid, tetracosapentaenoic
`acid, tetracosahexaenoic acid, monounsaturated fatty
`acids, polyunsaturated fatty acids, saturated fatty
`acids, trans fatty acids, derivatives thereof, and mix(cid:173)
`tures thereof, said tetracycline having a purity of at
`least 90% and a concentration of degradation prod(cid:173)
`uct(s) less than about 10% of the starting concentra(cid:173)
`tion of said tetracycline, wherein said purity and
`concentration of degradation product(s) are sufficient
`to permit safe treatment of said human patient; and
`
`[0051] an external gelatin layer comprising gelatin
`and additional components selected from the group
`consisting of an additional gelling agent, a plasti(cid:173)
`cizer, water, a colorant, an antioxidant, a fiavorant,
`and mixtures thereof.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0052] Definitions
`
`[0053] As used herein, "administering" refers to providing
`a composition orally or to a body orifice of a patient being
`
`treated. The term administering as used herein excludes
`providing a composition to a patient either intravenously or
`via inhalation.
`
`[0054] As used herein, a "controlled release" refers to a
`release rate that is different from the pharmacologically
`active agent's normal release rate. Accordingly, this term
`indicates that the release rate of the pharmacologically
`active agent has been modified to achieve a delayed, sus(cid:173)
`tained, or extended release in comparison to the agent's
`normal release rate.
`
`[0055] As used herein, "degradation products" refers to
`the product(s) produced by decomposition of one or more of
`the active ingredients of the present compositions.
`
`[0056] The phrase "effective amount", as used herein,
`means an amount of a composition or component thereof
`sufficient enough to positively modify the disorder to be
`treated but low enough to avoid secondary infections that
`cause a need for additional treatments beyond those con(cid:173)
`templated herein. Effective amounts will vary with the
`particular disorder or disorders being treated, the severity of
`the disorder, the duration of the treatment, the specific
`components of the composition being used, the weight,
`tolerance, and other physical attributes of the patient being
`treated, and like factors as are known by health-care pro(cid:173)
`viders, including physicians.
`
`[0057] As used herein, a "hard" oral dosage form refers to
`a solid oral drug delivery system formed for example via
`compression, direct or otherwise, granulation, and/or spray
`drying. For example, such a hard oral dosage form can be
`formed by compression of one or more powdery substances.
`Hard tablets, caplets, and pellets included in capsules are
`non-limiting examples of such hard oral dosage forms.
`
`[0058] As used herein, "pharmaceutically acceptable
`salts" refers to salts of the active compound(s) which
`possess the same pharmacological activity as the active
`compound(s) and which are neither biologically nor other(cid:173)
`wise undesirable. A salt can be formed with, for example,
`organic or inorganic acids. Non-limiting examples of suit(cid:173)
`able acids include acetic acid, acetylsalicylic acid, adipic
`acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid,
`benzenesulfonic acid, bisulfic acid, boric acid, butyric acid,
`camphoric acid, camphorsulfonic acid, carbonic acid, citric
`acid, cyclopentanepropionic acid, digluconic acid, dodecyl(cid:173)
`sulfic acid, ethanesulfonic acid, formic acid, fumaric acid,
`glyceric acid, glycerophosphoric acid, glycine, glucohep(cid:173)
`tanoic acid, gluconic acid, glutamic acid, glutaric acid,
`glycolic acid, hemisulfic acid, heptanoic acid, hexanoic acid,
`hippuric acid, hydrobromic acid, hydrochloric acid,
`hydroiodic acid, hydroxyethanesulfonic acid, lactic acid,
`maleic acid, malic acid, malonic acid, mandelic acid, meth(cid:173)
`anesulfonic acid, mucic acid, naphthylanesulfonic acid,
`naphthylic acid, nicotinic acid, nitrous acid, oxalic acid,
`pelargonic, phosphoric acid, propionic acid, saccharin, sali(cid:173)
`cylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric
`acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid,
`tosylic acid, undecylenic acid, naturally and synthetically
`derived amino acids.
`
`[0059]
`If organic bases are used, poorly volatile bases are
`preferably employed, for example low molecular weight
`alkanolamines such as ethanolamine, diethanolamine,
`N -ethylethanolamine, N -methyldiethanolamine, triethanola-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1018, Pg. 5 of 14
`
`

`

`US 2005/0158377 Al
`
`Jul. 21, 2005
`
`5
`
`mine, diethylaminoethanol, 2-amino-2-methyl-n-propanol,
`dimethylaminopropanol,
`2-amino-2-methylpropanediol,
`and
`triisopropanolamine. Further poorly volatile bases
`which may be mentioned are, for example, ethylenediamine,
`glucosamine, hexamethylenediamine, morpholine, piperi(cid:173)
`dine, piperazine, cyclohexylamine, tributylamine, dodecy(cid:173)
`lamine, N,N-dimethyldodecylamine, stearylamine, oley(cid:173)
`lamine, benzylamine, dibenzylamine, N-ethylbenzylamine,
`dimethylstearylamine, N-methylmorpholine, N-methylpip(cid:173)
`erazine, 4-methylcyclohexylamine, and N-hydroxyethyl(cid:173)
`morpholine.
`
`[0060] Salts of quaternary ammonium hydroxides such as
`trimethylbenzylammonium hydroxide, tetramethylammo(cid:173)
`nium hydroxide, or tetraethylammonium hydroxide can also
`by used, as can guanidine and its derivatives, in particular its
`alkylation products. However, it is also possible to employ
`as salt-forming agents, for example, low molecular weight
`alkylamines such as methylamine, ethylamine, or triethy(cid:173)
`lamine. Suitable salts for the compounds to be employed
`according to the present subject matter are also those with
`inorganic cations, for example alkali metal salts, in particu(cid:173)
`lar sodium, potassium, or ammonium salts, alkaline earth
`metal salts such as, in particular, the magnesium or calcium
`salts, as well as salts with bi- or tetravalent cations, for
`example the zinc, aluminum, or zirconium salts. Also con(cid:173)
`templated are salts with organic bases, such as dicyclohexy(cid:173)
`lamine salts; methyl-D-glucamine; and salts with amino
`acids, such as arginine, lysine, and so forth. Also, the basic
`nitrogen-containing groups can be quaternized with such
`agents as lower alkyl halides, such as methyl, ethyl, propyl,
`and butyl chlorides, bromides, and iodides; dialkyl sulfates,
`such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long
`chain halides, such as decyl, lauryl, myristyl, and stearyl
`chlorides, bromides, and iodides; asthma halides, such as
`benzyl and phenethyl bromides; and others. Water or oil(cid:173)
`soluble or dispersible products are thereby obtained.
`
`[0061] As used herein, "softgel", "soft gel", and "soft
`gelatin" can be used interchangeably and all refer to cap(cid:173)
`sules having a one-piece, hermetically sealed shell wall, or
`external layer, filled with oils and/or other aqueous or
`non-aqueous liquids, plus solids dispersed therein, either in
`solution or otherwise.
`[0062] As used herein, "treating" or "treatment" means the
`prevention or reduction of severity of symptoms or effect of
`a dermatological disorder, disease, infection, allergy, reac(cid:173)
`tion, or other dermatological condition.
`
`[0063] Other terms as used herein are meant to be defined
`by their well-known meanings in the art.
`
`[0064] Soft Gel Capsules
`
`[0065] According to the preferred methods and composi(cid:173)
`tions herein, a softgel, or soft gelatin, capsule is adminis(cid:173)
`tered to a mammal to provide a therapeutically effective
`amount of a pharmacologically active agent in order to treat
`a dermatological disease in said mammal. Preferred methods
`in this regard relate to methods of treating a dermatological
`disorder in a mammal comprising administering to said
`mammal a soft gel capsule providing a therapeutically
`effective amount of a pharmacologically active agent.
`
`[0066]
`In a preferred embodiment, the soft gel capsule
`comprises an internal phase and an external phase. The
`internal phase is preferably an internal, non-aqueous liquid
`
`phase comprising a solution or suspension of a pharmaco(cid:173)
`logically active agent or a salt or derivative thereof having
`a purity of at least 90% and a concentration of degradation
`product(s) less than about 10% of the starting concentration
`of the pharmacologically active agent. This purity level and
`concentration of degradation product(s) are sufficient to
`permit safe treatment of the dermatological disorder and
`provide improved bioavailability of the pharmacologically
`active agent.
`
`[0067]
`In a further preferred embodiment, the external
`phase is an external gelatin and/or soft cellulose layer.
`
`[0068]
`In another preferred embodiment, the pharmaco(cid:173)
`logically active agent used in the soft gel capsule is selected
`from the group consisting of antibiotics, antiinfectives,
`antim